Silencing of ERRα gene represses cell proliferation and induces apoptosis in human skin fibroblasts

Mol Med Rep. 2025 Jan;31(1):6. doi: 10.3892/mmr.2024.13370. Epub 2024 Oct 25.

Abstract

Estrogen‑related receptor (ERR) is an orphan nuclear receptor structurally akin to the estrogen receptor. ERR is expressed in tissues with active energy metabolism and regulates intracellular metabolic functions. Additionally, ERRs are known to be strongly expressed in the epidermis of skin tissue, but their functions are unknown. The present study investigated the function of ERRα in human skin fibroblasts. ERRα expressed in human dermal fibroblast TIG113 was knocked down using small interfering (si)RNA and gene expression was comprehensively analyzed using microarrays 48 h later. Pathway analysis was performed using Wikipathways on genes exhibiting expression changes of ≥1.5‑fold. Expression of cell cycle‑related and apoptosis‑related genes was compared using reverse transcription‑quantitative PCR. After treating TIG113 cells with siERRα for 72 h, cell proliferation was assessed using the Cell Counting Kit‑8 or a scratch wound healing assay and apoptotic cells were measured using the Poly Caspase Assay Kit. Cell cycle analysis was performed using flow cytometry. The expression of the ERRα gene was suppressed by siRNA. The expression of genes associated with cell cycle‑related pathways were decreased while that of those associated with apoptosis‑related pathways increased. Furthermore, the expression of cell cycle‑related genes such as cell division cycle 25C, cyclin E and cyclin B1 was decreased and the expression of apoptosis‑related genes such as caspase3 and Fas cell surface death receptor was increased. Cell proliferation was suppressed and the number of apoptotic cells increased ~2‑fold in ERRα‑knockdown TIG113 cells. Cell cycle analysis revealed that the number of cells in the Sub‑G1 phase increased and that in the S and G2/M phases decreased. The present study suggested that ERRα is an essential for the survival of human skin fibroblasts.

Keywords: apoptosis; cell proliferation; estrogen‑related receptor α; skin fibroblast.

MeSH terms

  • Apoptosis* / genetics
  • Cell Cycle / genetics
  • Cell Line
  • Cell Proliferation* / genetics
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • ERRalpha Estrogen-Related Receptor*
  • Fibroblasts* / metabolism
  • Gene Expression Regulation
  • Gene Silencing
  • Humans
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Estrogen* / genetics
  • Receptors, Estrogen* / metabolism
  • Skin / cytology
  • Skin / metabolism

Substances

  • Receptors, Estrogen
  • ERRalpha Estrogen-Related Receptor
  • RNA, Small Interfering
  • Cyclin E

Grants and funding

The present study was partly supported by the Japan Society for the Promotion of Science KAKENHI (grant nos. 20K02402 and 23K02038).